Death receptor of the tumor necrosis factor receptor (TNFR) family play fundamental roles in the development and functions of the immune system, by their ability to regulate programmed cell death or apoptosis. In this application it is proposed to stud the mechanism of signal transduction by the newly discovered TRAIL receptors (DR4, DR5, TRAIL-R3, TRAIL- R4) which belong to the TNFR family, and their role in the sensitivity of tumor cells and resistance of normal cells to TRAIL-induced apoptosis is controlled by a balance between the levels of the death promoting receptors, DR4 and DR5, and the death antagonist decoy receptor TRAIL- R3 and TRAIL-R4. Second, sensitivity of cells to TRAIL-induced apopptosis is also controlled by endogenous apoptosis inhibitory molecules such as FLAME (FLIP) and members of the anti-apoptotic Bcl- 2 family. Third, apoptosis signaling by DR4 and DR5 requires an adaptor molecule distinct from FADD/Mort-1, that could also play a role in the sensitivity of cells to TRAIL-induced apoptosis by analyzing the level of expression of these receptors I various tumor cells to TRAIL-induced apoptosis by analyzing the level of expression of these receptors in various tumor cell lines as well as in normal tissues or cells. Finally, it is proposed to analyze the role of specific antiapoptotic proteins in regulating the TRAIL signaling pathway, and identify and clone the interacting partner (s) of DR4 and DR5. It is anticipated that these studies will contribute to elucidation of the mechanism of signaling by TRAIL-receptors and their biological functions. This could lay the foundation for new therapeutic approaches to cancer.